Osteoporosis is one of the most important diseases associated with aging and is also one of the most important issues affecting women's health. Fractures due to osteoporosis exact a staggering toll in disability and expense. For a 50-yr-old white women, the lifetime risk of having one or more fractures associated with osteoporosis is 40% to 50% and is about one- third of this for white men or black women. Each year in the United States, there are at least 1.3 million fractures due to osteoporosis, which cost the healthcare system between $10 and $20 billion and, unless the disease is controlled, these will double over the next 25 yrs because of continued aging of the population. The long-range goal of this Program Project is to understand better the causes of age-related bone loss in osteoporosis an, by so doing, to develop effective strategies for its treatment and prevention. The Program Project contains 4 independent research components, each representing a different research discipline, and an administrative and biostatistical core. "Pathophysiology of Involutional Osteoporosis,' is the clinical investigative component. In this project, normal women will be studied to understand better the two most important causes of involutional bone loss -- estrogen deficiency and age-related processes. Also, women with postmenopausal osteoporosis will be studied to determine if their greater levels of bone turnover and rates of bone loss are due to unique processes that differ substantially from those in comparable women without osteoporosis. All studies will be made in a metabolic ward and will combine traditional physiologic methods with state-of-the-art techniques. "Record Studies of Hip Fractures," is the epidemiology component. It features a series of unique population-based, retrospective (noncurrent, historical) cohort studies designed to assess the effects of certain diseases, drugs, and lifestyle differences on the incidence of fractures. Also, secular changes in age-adjusted fracture rates over the last 20 yrs will be assessed. "Regulation of Bone Cell Function," is the basic science component. It uses cell biology and molecular biology techniques to evaluate the effects of estrogen on the differentiation and expression of growth factors on cultured normal osteoblast-like cells derived from bone or bone marrow and on a unique new cell line derived from normal undifferentiated fetal osteoblast-like cells immortalized with a temperature sensitive/regulated SV-40 large T antigen. Also, estrogen regulation of osteoblast-derived paracrine factors that regulate osteoclastic activity will be identified and characterized. "Preventive Therapy with Calcium," is an ongoing clinical trial, which will require a 1-yr extension to complete. It is designed to determine if bone loss in elderly women can be prevented or reduced by calcium supplementation.